Organic Letters
Letter
tioselectivities were all observed when the reactions were
performed in the presence of water (3.0 equiv) with L3 and
L6−L9 as the ligands (entries 14−17, 19). The best results
were achieved with L9 as the ligand and water as the additive.
The chiral spiro ketone was isolated in 98% yield with 92% ee
(entry 19). A gram-scale experiment was also performed under
similar conditions in the presence of 0.5 mol % Pd2dba3 and
1.2 mol % L9, and the product 2a (0.75 g, 98% yield) was
isolated with 92% ee, demonstrating the good scalability of the
asymmetric cyclization. To understand the pronounced water
effect, a reaction with NaOH as the base was conducted to
replace the NaOtBu/H2O system, and product 2a was
obtained with 86% ee, demonstrating the importance of the
hydroxyl anion for the high enantioselectivity. A further
variation of the water amount in NaOtBu/H2O system showed
little influence on the reaction (entries 18 and 20). The use of
toluene as the solvent also formed 2a in high yield but with
much diminished enantioselectivity (entries 21 and 22).
We then looked into the scope of the Pd-catalyzed
intramolecular α-arylation. Under optimized conditions in
THF using L9 as the ligand, NaOtBu as the base, and water as
additive, a series of chiral spiro[indene-1,2′-naphthalen]-1′-
ones 2b−k containing a spiro quaternary stereocenter were
formed in good yields with excellent enantioselectivities
(Scheme 2). Substrates 1b−f with either an electron-neutral,
-withdrawing, or -donating substituent on the bromoaryl ring
at the para or meta position were all applicable. High yields
and good ee values were also achieved on products 2g−i with
either an electron-withdrawing or -donating substitutent on the
3,4-dihydronaphthalen ring at various positions. Products 2j−k
containing substituents on both phenyl rings were also formed
in good yield with good ee. Pyridyl bromides 1l−m were also
suitable, providing the spirocyclic products 2l−m in moderate
yield with decent ee. A thiophene-containing product 2n was
also formed in 98% yield with a moderate ee (58%). It should
be noted that spirobi[inden]-1′-one 2o and spiro[benzo[7]-
annulene-6,1′-inden]-5-one 2p were also successfully synthe-
sized in nearly quantitative yields (98%) with good
enantioselectivities (84 vs 90% ee).
Scheme 2. Scope of the Enantioselective Pd-Catalyzed
Intramolecular α-Arylation
a
a
Unless otherwise specified, all reactions were performed under
nitrogen at 70 °C for 24 h with 1 (0.2 mmol), Pd2dba3 (2.5 mol %),
L9 (6 mol %), NaOtBu (1.5 equiv), H2O (3.0 equiv), and THF (2
mL). Isolated yields after silica gel column chromatography. ee values
were determined by chiral HPLC. The absolute configurations were
assigned by analogy to 2a.
also cyclized to form the spiro[indene-1,3′-piperidin]-2′-one
2aa in 61% yield with 68% ee.
To further demonstrate the generality of the enantioselective
α-arylation, 2-(2-bromophenethyl)cyclohexan-1-one 1q and its
derivatives were subjected to the asymmetric catalytic reaction
under similar reaction conditions (Scheme 3). Encouragingly,
spiro[cyclohexane-1,1′-inden]-2-one (2q) was formed in 75%
yield with 85% ee. Thus both the fluoro-substituted product 2a
and the methoxy-substituted derivative 2s were formed with
good ee’s (89% and 87%), although the yields were slightly
diminished (63 and 46%). A set of chiral spirocycles 2t, 2u,
and 2w were synthesized in 60−64% yield with 74−78% ee.
Surprisingly, the aryl bromide bearing a fluoro substituent at
the meta position led to a sharp decrease in yield (47%) and ee
(51% ee). Product 2w with a chloro substituent can also be
formed. Spiro[cyclopentane-1,1′-inden]-2-one (2x) was also
afforded in a moderate yield (61%) with a moderate ee (67%
ee). The intramolecular arylation of an ortho-substituted
substrate 1y also proceeded with L9 as the ligand but with no
enantioselectivity. Pleasingly, (R,R)-Me-BI-DIME (L2) proved
to be more effective in this case, leading to the formation of 2y
in 54% yield with 74% ee. Accordingly, the dimethoxy-
substituted chiral spirocycle 2z was also prepared in 64% yield
with 83% ee (Scheme 4). By using L10 as the ligand, LiHMDS
as the base, and toluene as the solvent, amide substrate 1aa was
The high enantioselectivities observed in the intramolecular
α-arylation with ligand L9 and the pronounced water effect
deserve further elaboration. Mechanistically, the L9-palladium-
(0) species I presumably undergoes oxidative addition with 1a,
forming the palladium(II) species II. Ligand exchange under
basic conditions forms the palladium(II) enolate III or α-
pallado ketone IV, which, after reductive elimination, forms
product 2a and regenerates the palladium(0) species I. The
stereochemistry of 2a is presumably determined in the stage of
species IV (Figure 2). Because of the well-defined structure of
the P-chiral phosphorus ligand L9, the conformation of its
palladium(II) complex IV is highly predictable.12a−d,13,14 As
depicted in both conformers A and B, the P-chiral ligand L9
has unambiguously defined the direction of palladium
coordination, and its lower phenyl ring together with two
trimethoxy-substituted benzene rings has effectively blocked
the entire back face. The substrate coordinates with the
palladium center through both aryl and α-carbonyl positions,
with its backbone facing the top to avoid interaction with the
aryl rings of the ligands. The T-shaped palladium(II) complex
in conformer B would have more steric interaction between
the aryl ring of the substrate and the tert-butyl group of the
ligand, whereas the more favorable conformer A proceeds via
C
Org. Lett. XXXX, XXX, XXX−XXX
Wu, Ting
